Over 50 million Americans are affected by osteoarthritis (OA). Increasingly OA is viewed as a metabolically active joint disorder of multiple etiologies. It imparts a substantial toll on the healthcare system and leads to compromised quality of life. Biochemically it is characterized by changes in the cartilage matrix macromolecules. Current treatment methods mainly offer symptomatic relief but these neither halt nor cure the disease. If the disease is detected early, (before the manifestation of gross morphological changes) therapeutic I interventions may stop its progression. These early changes are primarily associated with changes in proteoglycan (PG) and water content of cartilage. However, currently there is no nomnvasive method that is capable of detecting these changes. Lack of these diagnostic tools also hampered the research in drug development and evaluation of efficacy of the potential chondroprotective therapies. This demands a noninvasive probe that targets the measurement of cartilage PG, water content and volume. In this proposal, multinuclear magnetic resonance (MR) approaches that integrate the measurement of early biochemical changes with techniques that measure morphological changes are being developed. First, we propose to develop and optimize MR methodologies for quantifying water content and volume of cartilage in vitro and in vivo. Secondly, using sodium and proton MRI, (i) measure the macromolecular depletion induced changes in cartilage PG, water content and volume in vitro and establish a correlation between these parameters (ii) measure the PG and water content in human cartilage specimens with varying degree of degeneration and correlate the changes in PG and water content. Finally, sodium and proton MR will be optimized for clinical settings and then measure cartilage P0, water content and volume in healthy human subjects. Following these measurements, correlations between the cartilage parameters will be determined. Once the aims are accomplished, not only will a noninvasive tool become available to measure early biochemical changes, but also the ability to provide information about possible correlation between the biochemical and morphological changes. This will be the first time this approach is being developed and will have substantial impact on the both scientific and clinical studies of early OA, and on the chondroprotective drug development and evaluation.